The highly developed motor and mental function of human beings are controlled by a complicated communication network of a large number of nerve cells (neurons).
In this neural network, activity of each neuron (electrical signal) is transmitted to the target neurons through the neurotransmitter (chemical signal) released to the terminal junctions of the neuron (synaptic cleft). The neurotransmitter is stored within vesicles (synaptic vesicles) present at the nerve terminal and when a depolarization occurs due to an electrical activity of the neuron, the calcium channel at presynaptic membrane is opened and the neurotransmitter is then released by an influx of extracellular calcium ion into the nerve terminal. The neurotransmitter diffuses into the synaptic cleft, reaches the receptor at postsynaptic membrane of the target neuron, and then opens its sodium channel to cause new electrical activity. Since the type of neurotransmitter to be released has already been determined at each synapse and the affinity of each neurotransmitter for its receptor has also been determined, a specific information is transmitted through the intrinsic pathway in the network.
As a type of the neurotransmitters, a great variety of substances are known such as amines, amino acids and neuropeptides. Recently, it has been pointed out that glutamic acid, belonging to amino acid-type neurotransmitter, plays an important role in memory and motor function. For example, reduction of a long-term potentiation (phenomenon wherein an electrical response of neurons for a temporal electrical stimulation after tetanic stimulation is maintained for a long term) in hippocampus and impairments of spatial memory were observed in the mice that lacks .epsilon.1 subunit of the glutamic acid receptor (NMDA receptor), and it is therefore suggested that glutamic acid is involved in neural plasticity and memory formation. (Nature, Jan. 12, 1994, p.151). Additionally, in the mice in which metabolic glutamic acid receptor-1 (mGluR1) had been deleted, abnormal motor activity and impairment of spatial memory were also observed although there was little anatomical and electrophysiological difference between this deficit and normal mice (Nature, Nov. 17, 1994, p.237).
Furthermore, the following evidences are reported, which support the influences of glutamic acid in the brain on memory and motor function.
(1) A large number of neurons which uses glutamic acid as a neurotransmitter (glutamatergic neurons) are located in hippocampus and cerebellum that is closely involved in learning and memory.
(2) A modulation of transmission efficacy at the synapse, which would be involved in fundamental mechanism of learning and memory, is plastically occurred in a synapse wherein glutamic acid is used as a neurotransmitter. That is, it is known that phenomenon such as long-term potentiation or long-term depression is occurred in a postsynaptic membrane followed by a temporal modulation of an input induced by glutamic acid.
(3) Rats with bilateral lesions of hippocampus or with intraventricular administration of an antagonist for glutamic acid receptor (NMDA receptor) to inhibit an activity of the glutamic acid in the brain, can not learn the position of a platform in the water in the spatial learning of Morris's water maze task (Nature, Feb. 27, 1986, p.774).
Reviewing these evidences, it is considered that a reduction of glutamic acid activity in the brain causes an impairment of the transmission due to reduced excitation in neurons and then causes symptom of memory impairment such as dementia. Alternatively, it is also considered that, when an excess activity of glutamic acid influences motor neurons, it causes motor disturbances such as epilepsy. Accordingly, it is expected that these diseases can be prevented or improved by potentiating the reduced transmission or inhibiting the excess activity, respectively.
Accordingly, the object of the present invention is to provide the activity-potentiator and activity-inhibitor for the glutamic acid in the brain.